Project Abstract The blossoming diabetes, obesity and metabolic syndrome epidemics have taken a toll on the North American liver. The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD), whose genesis is in simple steatosis, and non-alcoholic steatohepatitis (NASH), are staggering. Left untreated, NASH can progress to NASH with increasing levels of fibrosis, cirrhosis and hepatocellular carcinoma (HCC). This disease continues to present a challenge to the gastroenterologist who has few, if any, combat-ready tools at his/her disposal. While a number of promising agents are in clinical trials in NASH, none has met approval. Liver disease is a chronic indication that will necessitate a long course of therapy, which brings with it the attendant risk of drug related side effects. The proposed program seeks to advance a highly targeted therapeutic, that is both, potentially effective, and potentially safe, for the treatment of NASH. This program is based on new information on the biology governing liver fibrosis, viz. the Rho-associated coiled-coil kinase (ROCK)2-hepatic stellate cell (HSC)-fibrosis (ROCK2-HSC-fibrosis) axis and the synthesis of ANG4201, a proprietary, orally bioavailable, small molecule inhibitor that can potentially interrupt this cascade. Under the aegis of this SBIR Phase I application, we will first obtain a profile of ANG4201 pharmacokinetics (PK), and its exposure-IC50 relationship (Specific Aim # 1). In Specific Aim # 2, we will use these data to evaluate the efficacy of ANG4201 in two etiologically distinct models of liver disease. Unlike the first generation of dual ROCK (1 &2) inhibitors, it is anticipated that a selective ROCK2 inhibitor will not only prove efficacious in mitigating fibrosis but will also carry a lower risk of any side effects associated with chronic dosing.